Several non-invasive methods of imaging body organs have been developed over the past decades. These methods are based on the tendency of particular body organs to concentrate particular chemicals which may be detectable. Particularly useful chemicals for these methods are those which emit gamma radiation. Subsequent scanning of the organ with a gamma ray camera provides an image of the organ from which diagnostic information can be obtained. .sup.99m Tc (Tc-99m) has found particular utility in this area because of its half-life and gamma ray emission.
Over the past several years different Tc-99m compounds have been disclosed for use as positive myocardial imaging agents. These different imaging agents based on substantially different chemistries, have exhibited varying levels of utility in different mammals. To effectively image the heart, the agent must localize in the heart and at the same time rapidly clear from neighboring organs such as the lungs and in particular the liver. Further, the imaging agent must not bind tightly to the blood or else image quality will be poor. An imaging agent which localizes in the heart and at the same time localizes in the liver does not provide a good image of the heart since the apex of the human heart is often obscured by the liver.
Although detecting radiation from a radiation emitting pharmaceutical has proven particularly useful in non-invasive organ imaging, organ-specific radio-pharmaceuticals are still needed. For example, there is an especially strong need for an effective myocardial imaging agent. At the present time there are two known types of myocardial imaging agents. The positive agents which accumulate in an infarcted area of the heart and negative agents which accumulate in the normal healthy area of the heart but not in the infarcted areas. Using a positive agent causes an infarcted area to show up as a hot spot of radioactivity whereas with a negative agent the infarcted area shows up as a cold area against a hot background.
Over the past several years different Tc-99m compounds have been disclosed for use as positive myocardial imaging agents. These different imaging agents having substantially different chemistries have found various levels of utility in different mammals. To date it is still a goal of nuclear medicine to find a more effective negative myocardial imaging agent particularly suited for the human heart.
Work with myocardial imaging agents formed from Tc-99m was conducted by Deutsch, et al. as disclosed in U.S. Pat. No. 4,489,054. Deutsch, et al. determined that cationic lipophilic complexes of Tc-99m provide a useful myocardial image in mammals. This work provided particularly good images with certain mammals, particularly dogs. Technetium can assume several valence stages ranging from +7 to -1. The method disclosed in the Deutsch, et al. U.S. Pat. No. 4,489,054 disclosed technetium complexes in the +3 state. These subsequently were found to provide a relatively poor image of the human heart.
Further work conducted by Deutsch and Libson, et al. indicated that the complexes of Tc(I)-99m provided more useful heart images. These provided particularly good images of cat hearts. Unfortunately, with humans these images were obscured by accumulation of the technetium complex in the liver which interfered with obtaining a very good image of the heart. This information is disclosed in Deutsch, et al. U.S. Patent application Ser. No. 628,482 filed Jul. 6, 1984 incorporated in U.S. Pat. No. 4,795,626. Additional work disclosed in the Deutsch, et al. patent indicated that .sup.99m Tc(I) compounds ligated to phosphonate and phosphonite ligands cleared the liver more quickly and provided an even better myocardial image than prior compounds. However, the .sup.99m Tc(I) ligated compounds clear the liver exceptionally well, but do not clear from the blood to permit a useful image of the heart.
Other cationic ligated complexes of .sup.99m Tc are disclosed, for example, in Rodriquez U.S. Pat. No. 4,497,790; Glavan, et al. U.S. Pat. No. 4,374,821; and Tweedle U.S. Pat. No. 4,455,291. Other technetium compounds are disclosed in European Patent Application 0123240.